TY - JOUR
T1 - Core-binding factor β interacts with Runx2 and is required for skeletal development
AU - Yoshida, Carolina A.
AU - Furuichi, Tatsuya
AU - Fujita, Takashi
AU - Fukuyama, Ryo
AU - Kanatani, Naoko
AU - Kobayashi, Shinji
AU - Satake, Masanobu
AU - Takada, Kenji
AU - Komori, Toshihisa
N1 - Funding Information:
We thank M. Yamamoto for the Gata1 promoter; Y. Ito for antibodies against Runx2 and Cbfβ; T. Kitamura for retroviral vector and Platinum-E; H. Harada for Runx2 and Cbfb cDNA; Y. Fujio for pACCMV.pLpA vector; A. Yamaguchi and M. Iwamoto for critically reading this manuscript; K. Sasaki, S. Bae and H. Enomoto for technical advice; R. Hiraiwa for maintaining mouse colonies; and M. Yanagita for secretarial assistance. This work was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - Core-binding factor β (CBFβ, also called polyomavirus enhancer binding protein 2β (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans. CBFβ forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFβ are essential for hematopoiesis. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb-/-) die at midgestation, so the function of Cbfβ in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb-/- mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb-/- mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfβ was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfβ is required for the function of Runx2 in skeletal development.
AB - Core-binding factor β (CBFβ, also called polyomavirus enhancer binding protein 2β (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans. CBFβ forms a heterodimer with RUNX1 (runt-related transcription factor 1), which has a DNA binding domain homologous to the pair-rule protein runt in Drosophila melanogaster. Both RUNX1 and CBFβ are essential for hematopoiesis. Haploinsufficiency of another runt-related protein, RUNX2 (also called CBFA1), causes cleidocranial dysplasia in humans and is essential in skeletal development by regulating osteoblast differentiation and chondrocyte maturation. Mice deficient in Cbfb (Cbfb-/-) die at midgestation, so the function of Cbfβ in skeletal development has yet to be ascertained. To investigate this issue, we rescued hematopoiesis of Cbfb-/- mice by introducing Cbfb using the Gata1 promoter. The rescued Cbfb-/- mice recapitulated fetal liver hematopoiesis in erythroid and megakaryocytic lineages and survived until birth, but showed severely delayed bone formation. Although mesenchymal cells differentiated into immature osteoblasts, intramembranous bones were poorly formed. The maturation of chondrocytes into hypertrophic cells was markedly delayed, and no endochondral bones were formed. Electrophoretic mobility shift assays and reporter assays showed that Cbfβ was necessary for the efficient DNA binding of Runx2 and for Runx2-dependent transcriptional activation. These findings indicate that Cbfβ is required for the function of Runx2 in skeletal development.
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U2 - 10.1038/ng1015
DO - 10.1038/ng1015
M3 - Article
C2 - 12434152
AN - SCOPUS:0036900947
VL - 32
SP - 633
EP - 638
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -